Relapsed/Refractory Patients:

Treatment Options - Doxil


Doxil® (doxorubicin HCL liposome injection)

 

NEWSFLASH: Latest Updates on Doxil

Janssen Products, LP additional supply of DOXIL® released to healthcare professionals (3/11/13). To learn about the latest updates, visit www.doxilsupply.com.

The U.S. Food and Drug Administration approved the first generic version of the cancer drug Doxil (doxorubicin hydrochloride liposome injection) (2/4/13). There continues to be full and unrestricted access to DOXIL®. For more information please visit: Doxorubicin.

 

Overview

Doxil in Relapsed or Refractory Patients

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What is Doxil?

Doxil is a chemotherapy drug used in cancer treatment. It is a reformulated version of doxorubicin (Adriamycin®), a cancer drug that has been used for many years in traditional chemotherapy regimens, including VAD (vincristine, Adriamycin, and dexamethasone) in myeloma.

In May 2007, Doxil was approved for use in combination with Velcade® (bortezomib, Millennium: The Takeda Oncology Company) to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy. Doxil is currently being evaluated in Phase III trials as a component of initial therapy for multiple myeloma.

Doxil is also known as doxorubicin HCl liposome injection or pegylated liposomal doxorubicin (PLD). It is distributed by Centocor Ortho Biotech Products, L.P. in the United States. Doxil was previously approved for the treatment of patients with ovarian cancer in 1999 and in patients with AIDS-related Kaposi’s sarcoma in 1995.

How is Doxil used in multiple myeloma?

For the treatment of myeloma, Doxil is typically used together with other anticancer agents. Doxil is often used in place of conventional doxorubicin, and it is also used as part of novel combination therapies.

Doxil is approved by the FDA for use in combination with Velcade to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy. Results of clinical trials show that that adding Doxil to a standard Velcade regimen reduced the risk of the disease progressing and prolonged the duration of response in patients with relapsed and refractory disease better than Velcade alone.

Doxil is being studied in combination with other approved myeloma drugs and in combination with new drugs in development for the treatment of relapsed and/or refractory myeloma. Doxil is also being studied as part of combination therapies for the treatment of newly diagnosed or previously untreated myeloma, also referred to as frontline therapy.

How does Doxil work?

Doxil is a reformulated version of the drug doxorubicin (Adriamycin®). Doxorubicin is a chemotherapy agent that belongs to a class of agents referred to as anthracyclines. Anthracyclines are used to treat cancer because they damage the DNA in cancer cells and cause them to die.

With Doxil, the doxorubicin is wrapped in a “fat bubble” (liposome), which serves to help slowly release the drug and may help reduce side effects. The liposomes are also coated with another substance, a process called pegylation, which helps the liposomes stay in the circulation longer.

How is Doxil given?

Doxil is given as an injection into a vein (intravenously, or IV). When used along with Velcade in the treatment of myeloma, the recommended dose is 30 mg/m2 Doxil administered over a 1-hour IV infusion. Velcade is administered as a 1.3-mg/m2 dose given on days 1, 4, 8, and 11, every 21 days. Doxil is given on day 4 following the Velcade dose.

It is recommended that Doxil be administered slowly at first (at an initial rate of 1 mg/min) to minimize the risk of infusion reactions. If no infusion-related side effects are seen, the infusion rate should be increased so that the process of administering the drug is completed in an hour.

Although there is limited information available on use of Doxil in patients with myeloma with reduced liver (hepatic) function, it is recommended that patients with hepatic impairment receive a lower dose of Doxil.

How long is the treatment with Doxil?

The length of treatment with Doxil may be different from patient to patient and is based on how well the drug is working and if the side effects are manageable. In general, patients are treated for up to 8 cycles until their disease progresses or if they experience unacceptable toxicity.

What are the possible side effects with Doxil?

It is important to remember that side effects of all treatments are based on the individual and vary from patient to patient. Doxil is associated with less frequent side effects than conventional doxorubicin. The most common side effects observed with Doxil therapy include:

  • A marked loss of strength, also referred to as asthenia
  • Fatigue
  • Fever
  • Gastrointestinal effects (ie, nausea, vomiting, diarrhea, and constipation)
  • Mouth sores, also referred to as stomatitis
  • Weight loss
  • Hand-foot syndrome (HFS), a skin condition marked by pain, swelling, numbness, tingling, or redness of the hands or feet
  • Rash
  • Low numbers of white blood cells known as neutrophils, a condition known as neutropenia
  • Low platelet counts, also referred to as thrombocytopenia
  • Anemia, or low numbers of red blood cells

In addition, reactions related to the intravenous administration of certain drugs, or infusion reactions, have been reported in up to 10% of patients treated with Doxil. The symptoms of an infusion-related reaction are usually mild to moderate and most commonly include chills, fever, nausea, weakness, headache, skin rash, and/or itching. In most cases, these reactions can be managed by either slowing or stopping the infusion.

Doxil may cause urine and other body fluids to turn a reddish-orange color. This nontoxic reaction is due to the color of the product and will go away as the drug is eliminated from the body.

Possible serious side effects of Doxil therapy

In general, any of the side effects of Doxil therapy listed above can sometimes be serious (Grade 3) or less commonly, very serious (Grade 4) in nature. Patients receiving Doxil are carefully monitored for these toxicities.

Although rare, severe infusion-related reactions, such as difficulty breathing or low blood pressure, may occur. These reactions require immediate treatment.

A potential side effect of long-term Doxil therapy is damage to the heart muscle (myocardial damage). Myocardial damage is related to the total dosage of doxorubicin a patient has received over time, which includes both conventional doxorubicin and Doxil. For this reason, it is generally recommended that patients receive a total of no more than 550 mg/m2 of doxorubicin over time. A lower total cumulative dose may be recommended if a patient has received radiotherapy to the area of the heart, or therapy with other agents that are potentially toxic to the heart, such as cyclophosphamide.

Fortunately, Doxil is potentially less toxic to heart muscle than conventional doxorubicin. This is mainly because there are much lower circulating levels of free doxorubicin in the blood when Doxil is used.

What are the possible side effects with Doxil-Velcade combination therapy?

The side effects seen with Doxil-Velcade combination therapy are similar to those seen with the individual drugs. In the DOXIL-MMY-3001 Phase III trial, which formed the basis for FDA approval of Doxil for use in myeloma, the most common side effects included:

  • Gastrointestinal effects (ie, nausea, diarrhea, vomiting, and constipation)
  • Peripheral neuropathy, a disorder of the nerves in the hands and feet
  • Fatigue
  • Low blood cell counts (neutropenia, thrombocytopenia, and anemia)
  • Fever
  • Rash
  • Asthenia
  • Stomatitis

The table below lists adverse reactions reported in 20% or more of patients treated with Doxil-Velcade or with Velcade alone for myeloma in the phase III DOXIL-MMY-3001 trial.

Adverse Events (Grade 1-4) Reported in at Least 20% of Patients
in the Phase III Doxil-Velcade Trial (DOXIL-MMY-3001)
Adverse Event Doxil + Velcade
(n=318)
Velcade
(n=318)
Nausea 48% 40%
Diarrhea 46% 39%
Peripheral neuropathy 42% 45%
Fatigue 36% 28%
Neutropenia 36% 22%
Thrombocytopenia 33% 28%
Vomiting 32% 22%
Constipation 31% 31%
Fever 31% 22%
Anemia 25% 21%
Rash 22% 18%
Asthenia 22% 18%
Stomatitis 20% 5%
Nerve pain/tingling/burning 17% 20%
Serious side effects seen with Doxil-Velcade combination therapy

In the Phase III trial that led to Doxil’s approval (DOXIL-MMY-3001), a number of patients with relapsed myeloma receiving Doxil-Velcade combination therapy experienced serious (Grade 3) or less commonly, very serious (Grade 4) side effects during the course of their treatment. These serious side effects included:

  • Neutropenia
  • Thrombocytopenia
  • Anemia
  • Fatigue
  • Asthenia
  • Diarrhea
  • Peripheral neuropathy
  • Hand-foot syndrome (HFS)

How are side effects of Velcade-Doxil managed?

Patients should notify their doctor if they experience any of the following symptoms:

  • Hand-foot syndrome: tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet
  • Stomatitis: painful redness, swelling, or sores in the mouth
  • Fever and neutropenia: fever of 100.5°F or higher
  • Other: nausea, vomiting, tiredness, weakness, rash, or mild hair loss

Your doctor may modify or delay your dose of Doxil if you experience hand-foot syndrome or stomatitis. Your dose of Doxil and/or Velcade may also be reduced or delayed if you experience fever, low blood cell counts, severe side effects, neuropathic (nerve) pain, or neuropathy.

The following table describes specific dosage adjustments for Doxil and Velcade combination therapy for myeloma if certain side effects occur.

Dosage Adjustments for Doxil-Velcade Combination Therapy
Patient Status Dose Adjustment
Doxil Velcade
Fever ≥38°C and
ANC* <1,000/mm3
Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25%. Reduce next dose by 25%
On any day of drug administration after Day 1 of each cycle:
  • Platelet count <25,000/mm3
  • Hemoglobin <8 g/dL
  • ANC <500/mm3
Do not dose this cycle if before Day 4; if after Day 4, reduce next dose by 25% in the following cycles if bortezomib is reduced for hematologic toxicity. Do not dose; if 2 or more doses are not given in a cycle, reduce dose by 25% in following cycles.
Grade 3 or Grade 4 nonhematologic drug-related toxicity Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses. Do not dose until recovered to Grade <2 and reduce dose by 25% for all subsequent doses.
Neuropathic pain or peripheral neuropathy No dosage adjustments needed. Adjust dose of Velcade according to recommended guidelines for dosage adjustments in patients with neuropathic pain.

*ANC = absolute neutrophil count (the total number of white blood cells in the blood that are neutrophils)

What types of patients can benefit from Doxil therapy?

Results of the Phase III trial that led to Doxil’s approval (DOXIL-MMY-3001) showed that the combination of Doxil and Velcade is effective in a wide range of patients with relapsed/refractory myeloma, including:

  • Older patients (≥65 years old) as well as younger patients
  • Patients who have previously received a stem cell transplant
  • Patients who have previously received Thalomid or Revlimid
  • Patients who have previously received doxorubicin
  • Patients with “high-risk” disease (poor prognosis)
    • Doxil was beneficial to patients with chromosome abnormalities and those with elevated levels of beta 2-microglobulin
  • Patients with impaired renal (kidney) function

Doxil in Relapsed and/or Refractory Myeloma

Is Doxil-Velcade effective in treating relapsed and/or refractory myeloma?

Doxil was approved in the United States for use in combination with Velcade to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy. The approval was based on results of a planned interim analysis of an international Phase III trial (DOXIL-MMY-3001) that compared the combination to Velcade alone in 646 patients with relapsed/refractory myeloma.

The results of this study show that showed that adding Doxil to the standard Velcade regimen reduced the risk of the disease progressing and prolonged the duration of response in patients with relapsed and refractory disease compared with Velcade alone.

  • The combination significantly extended the median time to disease progression (TTP) from 6.5 months to 9.3 months.
  • The 15-month survival rate for Doxil plus Velcade was 76% compared with 65% for Velcade alone.
  • The benefits of the combination were consistently seen across a variety of patient types, including older patients, those with prior stem cell transplantation or exposure to Thalomid or doxorubicin, and patients with markers of high-risk disease.

In addition to Velcade, what other drugs are being studied in combination with Doxil for the treatment of relapsed/refractory myeloma?

Doxil is being studied in combination with various approved and investigational agents for use in treating relapsed/refractory myeloma. For example:

  • The combination of Velcade, Doxil, and low-dose dexamethasone (PAd) appears to be active in relapsed/refractory myeloma.
  • Adding Doxil to Velcade, Thalomid, and dex therapy significantly improves outcome in advanced myeloma. Data from a single center show that adding Doxil increased the response rate, the time until disease progressed, and the length of time patients were living with myeloma that did not get worse.
    • The combination of Velcade, Doxil, and thalidomide has also been shown to be an effective steroid-free regimen for patients with relapsed or refractory myeloma.

To find a clinical trial, call 1-866-603-MMCT (-6628) or click here to go to the MMRF Patient Navigator Program.